Susan C. Fagan

Acute Hypertension, but Not Thrombolysis, Increases the Incidence and Severity of Hemorrhagic Transformation Following Experimental Stroke in Rabbits

Hemorrhagic transformation (HT) is a poorly understood yet frequent complication of stroke. A transient increase in blood pressure (BP) occurs immediately after experimental embolization in rabbits and we evaluated the relationship between this acute hypertensive response and subsequent hemorrhagic transformation, as well as the attenuation of this hypertensive response with an anesthetic dose of halothane. We also examined embolism-induced HT during infusion of the thrombolytic agents tissue plasminogen activator and streptokinase. A blood clot embolus was injected into the internal carotid artery and flushed into the middle cerebral artery. In the first experiment, BP was monitored in anesthetized or unanesthetized rabbits for 20 min prior to and up to 1 h after embolization. In the second experiment, animals were embolized half-way through an infusion of tPA (3.0 mg/kg; 20% administered as an iv bolus, with the remainder infused over 30 min) or streptokinase (30,000 U/kg iv infused over 30 min). In unanesthetized animals, the HT score (number of brain sections displaying visible HT) was significantly correlated with the peak mean arterial pressure recorded at embolization (r = 0.60, n = 24, P < 0.01). No relationship was observed between BP and HT score in animals anesthetized with halothane. Although HT incidence and extent were significantly related to elevated BP in the unanesthetized animals, halothane administration actually increased HT incidence. Embolization during thrombolytic infusion did not increase the occurrence or severity of HT. These data suggest that acute hypertension, but not ongoing thrombolysis, is a significant risk factor for HT following cerebral embolization.

Acute Hypertension Promotes Hemorrhagic Transformation in a Rabbit Embolic Stroke Model: Effect of Labetalol

We examined the relationship between acute hypertension following cerebral embolization and subsequent hemorrhagic transformation (HT) in a rabbit embolic stroke model. We have shown previously that the likelihood and severity of hemorrhage were significantly correlated with the magnitude of an acute hypertensive response to embolization. It was not clear, however, whether hypertension actually caused hemorrhage or was merely a marker of more severe stroke. In the current studies, we attempted to clarify the relationship between acute hypertension and HT by either pharmacologically inducing or attenuating the brief hypertensive response to embolization in rabbits. Under halothane anesthesia, two catheters were implanted in the right carotid arteries of male New Zealand white rabbits, one oriented toward the heart and one toward the brain. The animals were allowed to awaken and were embolized using blood clot emboli injected into the middle cerebral artery. Blood pressure was monitored via the second carotid catheter. In the first experiment, hypertension was induced with angiotensin II, administered at the time of embolization or 1 h later. In the second experiment, we attempted to attenuate the hypertensive response using intravenous labetalol. The animals were sacrificed 18 h after embolization and the brains evaluated for hemorrhage. In the first experiment, administration of angiotensin II immediately after embolization did not increase the hypertensive response to embolization further than that spontaneously occurring, and no angiotensin II-related HT was observed. In contrast, an additional angiotensin-II-induced hypertensive episode 1 h after embolization significantly increased the number of 5-mm serial brain sections displaying HT, from 3.0 +/- .3 (mean +/- SE) in Controls to 5.4 +/- .8 in treated animals. In the second experiment, administration of labetalol (15 mg/kg) significantly reduced the number of brain sections with visible HT, from 3.2 +/- .5 in controls to 1.6 +/- .4 in treated animals. Acute hypertension during the first hour after cerebral embolization promotes HT in this rabbit embolic stroke model. Labetalol prevents blood pressure elevation and reduces the extent of HT in the same model.

Risk of cerebral hypoperfusion with antihypertensive therapy

The effective treatment of hypertension is a major factor in the declining incidence of stroke in North America. There are subsets of patients, however, in which antihypertensive therapy may actually cause cerebral ischemia and infarction. Elderly patients and those with malignant hypertension, acute stroke, and occlusive cerebrovascular disease appear to be the populations at greatest risk of iatrogenic stroke. This article reviews the effect of beta-blockers, angiotensin-converting enzyme inhibitors, direct vasodilators, and calcium-channel blockers on cerebral blood flow in various populations. Although many investigations have been performed, it remains difficult to predict the risk of cerebral hypoperfusion due to antihypertensive medication in an individual patient. It is best for practitioners to be aware of the patient populations at risk and treat high blood pressure cautiously in these patients.The effective treatment of hypertension is a major factor in the declining incidence of stroke in North America. There are subsets of patients, however, in which antihypertensive therapy may actually cause cerebral ischemia and infarction. Elderly patients and those with malignant hypertension, acute stroke, and occlusive cerebrovascular disease appear to be the populations at greatest risk of iatrogenic stroke. This article reviews the effect of beta-blockers, angiotensin-converting enzyme inhibitors, direct vasodilators, and calcium-channel blockers on cerebral blood flow in various populations. Although many investigations have been performed, it remains difficult to predict the risk of cerebral hypoperfusion due to antihypertensive medication in an individual patient. It is best for practitioners to be aware of the patient populations at risk and treat high blood pressure cautiously in these patients.

Current Developments in Neurology, Part II: Advances in the Pharmacotherapy of Alzheimer Disease, Parkinson's Disease, and Stroke

Disorders of the central nervous system provide innumerable challenges to the clinician. Often the underlying pathophysiology is not completely understood, thus preventing the design of treatment strategies aimed at correcting the underlying process. In this decade of the brain, basic science research combined with difficult but necessary clinical trials may answer some of these seemingly over-whelming questions for these devastating illnesses.

Hemodynamic vertebrobasilar insufficiency as an adverse effect of antihypertensive therapy.

A 63-year-old white male with a 25-year history of hypertension experienced the onset of intermittent diplopia and gait disturbance 24 hours after a change in antihypertensive medication from atenolol 50 mg/d to enalapril 5 mg bid. Three weeks later, the patient was admitted with a worsening of symptoms. Cerebral arteriography revealed significant bilateral vertebral artery stenosis. Symptoms continued to progress in the hospital, and at the time of posterior circulation revascularization the patient had a persistent bilateral internuclear ophthalmoplegia and right ptosis. The need for a neurovascular workup and adjustment of therapy in patients with antihypertensive-associated cerebral ischemia is discussed.

Ticlopidine : a new antiplatelet agent for cerebrovascular disease

Ticlopidine is a new prototype antiplatelet drug chemically unrelated to currently available agents. It causes an alteration in platelet membrane reactivity to a variety of aggregating stimuli and a marked prolongation of bleeding time, the mechanism of which remains unclear. Two major phase III multicenter trials, the ticlopidine‐aspirin stroke study (TASS) and the Canadian‐American ticlopidine study (CATS) reported that the agent may reduce the occurrence of stroke, myocardial infarction, or vascular death in patients of both sexes who have had recent cerebral ischemia. Ticlopidine has been well tolerated in preliminary studies, with the most commonly described adverse effects being rash and gastrointestinal complaints. The most important adverse effect is neutropenia, which was reported in both TASS and CATS, approximating a frequency of 0.9% and 0.8%, respectively. Ticlopidine holds considerable promise as adjunctive therapy in selected patients.

Management of Hypertension in Stroke

This chapter discusses the management of hypertension in stroke. Hypertension is the single most important risk factor for stroke. In patients presenting with acute ischemic stroke, approximately 70% are hypertensive and approximately 50% of these patients have a history of chronic hypertension. Cerebral blood flow is maintained at a consistent rate by virtue of a process known as cerebral autoregulation. Autoregulation occurs through changes in cerebral vascular resistance leading to vasodilation when peripheral blood pressure is reduced and vasoconstriction when blood pressure is elevated. In addition to the high rate of chronic hypertension in acute stroke patients, a certain degree of acute or reactive hypertension occurs in the immediate poststroke period. Longitudinal studies have revealed that even without treatment, blood pressure will decrease in the first week. Hypertensive patients with cerebrovascular disease often have other chronic diseases which must be considered when determining the preferred antihypertensive agent. Diabetes mellitus, previous myocardial infarction, congestive heart failure and peripheral vascular occlusive disease are all common comorbidities which influence the choice of regimen. It is suggested that selection of a single agent which serves a dual therapeutic purpose offers advantages to the patient in both cost and convenience.

Transcranial Doppler to Evaluate the Effects of Antihypertensive Medication on Cerebral Blood Flow Velocity

The effect of oral nifedipine on cerebral blood flow velocity was studied in six elderly hypertensive patients using transcranial Doppler. Serial measurements of blood pressure (BP), middle cerebral artery (MCA) flow velocity and nifedipine serum concentrations were obtained over an 8‐hour period. The authors found a significant inverse relationship between MCA velocities and nifedipine concentrations, independent of BP changes. These results are consistent with a direct vasodilatory effect of nifedipine on cerebral vessels and support the use of TCD in pharmacodynamic investigations of the cerebral vasculature.

Current Developments in Neurology, Part I: Advances in the Pharmacotherapy of Headache, Epilepsy, and Multiple Sclerosis

When caring for patients with disorders of the central nervous system such as migraine headaches, epilepsy, or MS, clinicians are faced with increasingly complex pharmacotherapeutic options. Pharmacotherapeutic strategies directed toward prevention, reversal, or cure of these diseases are hampered by an incomplete understanding of the underlying pathophysiology. In this decade of the brain, basic science research combined with difficult but necessary clinical trials may answer some seemingly overwhelming questions for these devastating illnesses.

Age and carotid artery occlusive disease are important determinants of cerebral blood flow changes after antihypertensive therapy

Study Objective. To determine the short‐term effects of antihypertensive therapy on cerebral blood flow (CBF).